Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin-6 expression.
Nuclear factor kappa B (NF-kappaB) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF-kappaB transcriptional complexes. We have previously reported that nuclear expression of the NF-kappaB subunit p50 is strongly correlated with melanoma progression and poor 5-year patient survival. In this study, we used cDNA microarray to analyze the gene expression profiles of melanoma cells overexpressing NF-kappaB p50. We found that NF-kappaB p50 expression strongly induced interleukin-6 (IL-6) upregulation in melanoma cells at both the transcriptional and translational levels and that IL-6 production by melanoma cells enhanced the growth of endothelial cells in vitro. Expression of activating transcription factor 3 (ATF3), a negative regulator of IL-6 gene transcription, inhibited p50-mediated IL-6 upregulation. Knockdown of p50 expression using lentiviral-based shRNA abrogated IL-6 induction in melanoma cells and inhibited its effects on endothelial cell growth. Finally, we used an in vivo matrigel plug assay to show that NF-kappaB p50 overexpression promotes angiogenesis, while silencing NF-kappaB p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF-kappaB p50 subunit mediates melanoma angiogenesis by specifically upregulating IL-6, highlighting a novel and important role for the NF-kappaB p50/IL-6 signaling axis in melanoma progression.
Karst
Alison M
AM
Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Gao
Kai
K
Nelson
Colleen C
CC
Li
Gang
G
D051700:Activating Transcription Factor 3 / Q000096:biosynthesis; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D007797:Laminin / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D052002:NF-kappa B p50 Subunit / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000737:chemistry; D015854:Up-Regulation
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D004338:Drug Combinations; D015850:Interleukin-6; D007797:Laminin; D052002:NF-kappa B p50 Subunit; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen